lopamidol is one of the most used non-ionic iodinated X-ray contrast agents. In the manufacture of lopamidol a multi-step synthesis is involved.
Several methods have been disclosed in the literature for the synthesis of lopamidol. The methods first described for the preparation of lopamidol, as disclosed in GB1472050 and U.S. Pat. No. 4,001,323, introduced the chiral center by reacting 5-amino-2,4,6-triiodoisophthaloyl dichloride with (S)-1-chloro-1-oxopropan-2-yl acetate. One disadvantage appointed (see U.S. Pat. No. 7,282,607) to these methods is the introduction of the chiral center very early in the synthesis, however, it is more economically preferred to introduce the highly expensive reagent 2-amino-1,3-propanediol (serinol) as late as possible in the synthesis. In contrast other methods more recently described introduced the chiral center in the last steps of the synthesis, as disclosed in U.S. Pat. No. 7,282,607 and U.S. Pat. No. 7,368,101, including making esters of 5-amino-N1,N3-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide and other protecting strategies, followed by the reaction of the protected derivative with (S)-1-chloro-1-oxopropan-2-ylacetate. The last step of the synthesis removes all the groups introduced to protect the primary alcohols including the acetate from the chiral center thus affording lopamidol. Such methods release a high quantity of by products, making these methods less economically and environmentally friendly, atomically speaking. To overcome this drawback a method that includes less “atom usage”, as did the firstly described methods of GB1472050 and U.S. Pat. No. 4,001,323, is preferred. A method that uses fewer acyl chloride intermediates would also be preferred; as such methods would facilitate industrial operations.
Surprisingly, the method of the present invention meets the above needs and requirements by using 5-amino-2,4-6-triidoisophatalic acid as a starting material and introducing the chiral center in the first stage of the process by reaction with (S)-1-chloro-1-oxopropan-2-yl acetate thus forming the new compound, (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid. Furthermore, the method via the new compound allows the synthetic route to triiodinated contrast agents, such as lopamidol, to proceed without racemization, avoiding the use of protection/deprotection methodologies and introducing the highly expensive reagent serinol, immediately before the chemical step where lopamidol is obtained. Moreover lopamidol, is obtained in high purity, with a very low content of related process impurities such as acetyl and hydroxyacetyl analogs.